A small number of naturally occurring and engineered mutations in mice result in extension of lifespan. Functional growth hormone (GH) deficiency has been associated with increased longevity in at least four strains of mice, two of which, the Ames (Prop1df/df) and Little (Ghrhrlit/lit) mice, we have studied intensively. Global gene expression analysis of the liver in GH deficient, long-lived mice, as well as calorically restricted (and thus long-lived) mice, shows a correlation between increased lifespan and elevation of genes which belong to the category of xenobiotic or detoxification metabolism. Detoxification of endogenous metabolic intermediates is a major function of the liver. This pathway is comprised of transporters, cytochromes, transferases, and exporters which become transcriptionally regulated by nuclear hormone receptors (NHRs) upon activation of the NHRs by several endogenous compounds including bile acids, steroids, vitamins, and lipids. Long-lived mutants of C. elegans show similar elevations of NHRs, cytochromes, and transferases (23, 24) In this proposal, we will test the hypothesis that chronic activation of xenobiotic metabolism as seen in the GH deficient, long-lived mice, is beneficial to longevity. Specific Aim 1 will use a mutant mouse line (a knockout of cytochrome 7b1) that mimics the changes in detoxification pathways that are found in the long-lived mice. This knockout mouse model has patterns of elevation of xenobiotic metabolism genes similar to the GH deficient mice. The Cyp 7b1 null mice will be examined for longevity extension. Specific Aim 2 is designed to elucidate the molecular mechanisms that control the activation of the detoxification response genes by examining the requirement for NHRs in double and triple KO mice and by knockdown of specific NHRs and candidate transcription factors in the liver. Finally, the consequences of reduction of Stat Sab signaling in the liver will be assessed by gene expression arrays to determine whether or not a reduction in Stat Sab in the liver accounts for the majority of gene expression changes seen in the GH deficient Ames and Little mice, and to identify potential co-regulators. These aims will directly test whether or not chronic activation of xenobiotic metabolism impacts lifespan and will elucidate molecular targets that may be useful points of intervention in the aging process.